Synthesis of (1S,2R)-1-phenyl-2-[(S)-1-aminoalkyl]-N,N-diethylcyclopropanecarboxamides as novel NMDA receptor antagonists having a unique NMDA receptor subtype selectivity

Abstract

(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (2b), which is a conformationally restricted analog of the antidepressant milnacipran [(±)-1], is a new class of potent NMDA (N-methyl-D-aspartic acid) receptor antagonists. A series of analogs of 2b modified at the 1′-position were designed and synthesized starting from (R)-epichlorohydrin via the key intermediate an optically active cyclopropanecarbaldehyde derivative 8 with a (1S,2R)-configuration. Among these analogs, (1S,2R)-1-phenyl-2-[(S)-1-aminobut-3-enyl]-N,N-diethylcyclopropanecarboxamide (2i) and (1S,2R)-1-phenyl-2-[(S)-1-aminobut-3-ynyl]-N,N-diethylcyclopropanecarboxamide (2j) were identified as more potent NMDA receptor antagonists than 2b. The subtype selectivity of 2i and 2j together with 2b was investigated to show that 2i inhibited the GluRε3/ζl and GluRε4/ζl subtypes four times more strongly than GluRε1/ζl and GluRε2/ζl subtypes. Compound 2i is the first GluRε3/ζl and GluRε4/ζl subtype-selective antagonist, while the selectivity is not so high.